Pediatric brain cancer is an especially tough pill to swallow. While one in four children does not survive medulloblastoma, survivors are often plagued with long-term side effects from invasive treatment procedures which include surgery, whole-brain and spine radiation, and intensive chemotherapy. As a result of these treatments, children can suffer from intellectual disabilities, hormonal disorders and an increased risk of developing cancer later in life. While immunotherapy is an emerging alternative treatment option, individuals who have tumors with mutations in a gene that stops the growth of tumors, p53, are often insusceptible to immunotherapy. Now that might change.
New research published in Nature Neuroscience from scientists at Sanford Burnham Prebys has identified a technique that has shown to be successful in destroying medulloblastoma in mice. The technique combines traditional immunotherapy with a drug called tumor necrosis factor (TNF).
"I've studied medulloblastoma for more than 20 years. I've seen many therapies that prolong survival in mice. But this is the first time I have ever seen a therapy essentially melt the tumor away," says senior author Robert Wechsler-Reya, Ph.D., who is a professor and director of the Tumor Initiation and Maintenance Program at Sanford Burnham Prebys, and program director of the Joseph Clayes III Research Center for Neuro-Oncology and Genomics at the Rady Children's Institute for Genomic Medicine.
Mutations in the p53 gene are dangerous because p53 scans DNA for errors and is the most frequently mutated gene in human cancer. From their experiments on mice, the researchers figured out that tumors without p53 do not show protein known as the major histocompatibility complex I (MHC-I) on their surface. According to Eureka Alert, “MHC-I allows tumors to be recognized and killed by the immune system; without it, a tumor is invisible to the immune system and continues to grow uninterrupted.”
But administering a low dosage of TNF during immunotherapy can increase MHC-I to the levels needed for immunotherapy to work. "Our findings suggest that some cancers may not respond to immunotherapy because the tumors don't have sufficient MHC-I levels to trigger an effective immune response," says Wechsler-Reya. "Our hope is that in the near term, combining immunotherapy with TNF will increase the effectiveness of immunotherapy for children who are battling brain cancer."
The researchers think that their findings hold significant implications for the future of medulloblastoma treatment. "We are very encouraged by these study results and hope to initiate a Phase 1 clinical trial as soon as possible," says Sabine Mueller, M.D., Ph.D., co-founder of the Pediatric Pacific Neuro-Oncology Consortium (PNOC). "Undergoing chemotherapy and radiation is difficult for adults, and even more so for children. Treatment advances cannot come soon enough for these vulnerable pediatric patients."
"We look forward to testing this approach in the clinic and are hopeful that this discovery might be able to save children's lives,” concludes Wechsler-Reya.